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Four aces of heart failure therapy: systematic review of established and emerging therapies for heart failure with reduced ejection fraction

Ruffino, Enrico1; Gori, Mauro1; D’Elia, Emilia1; Sciatti, Edoardo1; Shi, Victor2; Senni, Michele1,∗

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doi: 10.1097/CP9.0000000000000007
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Heart failure with reduced ejection fraction (HFrEF) is a common disease with a poor prognosis with increasing prevalence in the community[1]. It requires multi-drug therapy for symptomatic and prognostic improvement.

Drug therapies, such as angiotensin receptor neprilysin inhibitors (ARNIs; ie, sacubitril/valsartan), beta-blockers, and mineralocorticoid receptor antagonists (MRAs), provide marked reduction in all-cause mortality, cardiovascular (CV) mortality, all-cause hospitalizations, and hospitalizations for heart failure (HF)[2].

A new therapeutic pillar (sodium-glucose-cotransporter 2 inhibitor; SGLT2i) was added to the standard three groups after the landmark DAPA-HF and EMPEROR-Reduced trials (Figure 1)[3]. According to the most recent international HF guidelines, the addition of dapagliflozin and empagliflozin to ACE inhibitors (ACE-Is)/ARNIs, beta-blockers, and MRAs reduced the risk of CV death and worsening HF in patients with HFrEF. Unless contraindicated or not tolerated, SGLT2is are strongly recommended for all patients with HFrEF already treated with optimal medical therapy, regardless of their diabetes status (Class I, Level A)[4].

Figure 1:
Four “Aces” of chronic HFrEF drug therapy.The current paradigm of sequential drug therapy recommends a multi-drug combination therapy upfront, including four “aces,” classes: beta-blocker, MRA, ARNI, and SGLT2i.ARNI: angiotensin receptor neprilysin inhibitors; MRA: mineralcorticoid receptor antagonists; SGLT2i: sodium-glucose-cotransporter 2 inhibitors.

The approach to HFrEF therapy is consequently shifting from a stepwise approach to upfront combination therapy of all four classes of drugs, that is, the “4 aces” approach.

The combined effect of multi-drug therapy has been demonstrated in an interesting cross-trial analysis[5] that compared a comprehensive disease-modifying pharmacological therapy regimen (ARNI, beta-blocker, MRA, and SGLT2i) with conventional therapy (ACEi/ARB and beta-blocker). The analysis included indirect comparisons of three pivotal trials: EMPHASIS-HF (n = 2737), PARADIGM-HF (n = 8399), and DAPA-HF (n = 4744). The imputed aggregate treatment effects of comprehensive disease-modifying therapy on reduced the risk of the primary endpoint of CV death or hospital admission for HF by a striking 62%. The hazard ratios for CV death, hospitalization for HF, and all-cause mortality were all remarkably low (0.50, 0.32, and 0.53, respectively). Use of full combination therapy afforded 2.7 additional years (for an 80-year-old patient) to 8.3 additional years (for a 55-year-old patient), free from CV death or first hospital admission for HF. The benefit of four classes combination therapy was evident against the “first step” therapy of de novo HFrEF, namely, ACEi/ARBs and beta-blockers, despite the first-step therapy approach being guideline-recommended and backed by a randomized clinical trial (RCT).

The bottom line is that combination therapy with all four classes of disease-modifying drugs, initiated as early as possible, yields substantial benefits and should be the standard of care (Figure 2).

Figure 2:
Projected mean event-free survival with comprehensive therapy (blue) versus conventional therapy (red), for patients starting at 55 years or 65 years.A, Patients starting at 55 years. B, Patients starting at 65 years. The sooner the full therapy is started; the more event-free years are gained (modified from Vaduganathan et al.[5]).

Thus, the aim of this review was to analyze the pivotal trials for each drug class, provide a short comment on how the findings of the trial can be implemented in clinical practice, and offer some tips and tricks on the practical management of each drug class. Key benefits from each “ace” are summarized in Table 1.

Table 1 - Effect of the four aces of HF on CV death, HF hospitalization and renal benefit
Drug class Trial Drug Comparator All-cause death CV death or HFH CV death alone HFH alone Renal benefit Other key relevant benefit
ARNI PARADIGM-HF [6] Sacubitril/valsartan (n = 4,187) Enalapril (n = 4,212) −16% −20% −20% −21% Composite renal outcome – 51% and slower rate of decrease in the eGFR Sudden death
SGLT2i DAPA-HF [39] Dapagliflozin (n = 2,373) Placebo (n = 2,371) −17% −25% −18% −30% CV mortality or worsening HF - 26%
EMPEROR-Reduced [40] Empagliflozin (n = 1,863) Placebo (n = 1,867) −25% −30% Composite renal outcome −50% Total hospitalization – 30%
SOLOIST-WHF [41] Sotagliflozin (n = 1,222) Placebo −33% −36%
EMPULSE [42] Empagliflozin (n = 530) Placebo −5.7%
MRA RALES [28] Spironolactone (n = 822) Placebo (n = 841) −30% −31% −35%
EMPHASIS-HF [31] Eplerenone (n = 1,364) Placebo (n = 1,373) −24% −37% −24% −42%
Beta-blockers COPERNICUS [33] Carvedilol (n = 1,156) Placebo (n = 1133) −35%
CIBIS-II [34] Bisoprolol (N = 1,327) Placebo (N = 1,320) −34% −21% −29% −36%
MERIT-HF [35] Metoprolol CR/XL (n = 1,991) Placebo (n = 2,001) −34% −38% Sudden death - 38%
SENIORS [36] Nebivolol (n = 1,067) Placebo (n = 1,061)
ARNI: angiotensin receptor neprilysin inhibitor; CV death: cardiovascular death; eGFR: estimated glomerular filtration rate; HF: heart failure; HFH: heart failure hospitalization; MRA: mineralocorticoid receptor antagonist; SGLT2i: sodium-glucose cotransporter 2.

We subsequently reviewed the evidence and pivotal trials for each “ace” drug class individually.


ARNIs are a new therapeutic class of agents acting on the renin-angiotensin-aldosterone system (RAAS) and the neutral endopeptidase system (ie, ARNI). The first molecule in this class is a combination of valsartan and sacubitril. Besides the beneficial effects of RAAS inhibition, ARNIs act through inhibition of neprilysin, blocking the degradation of A-type and B-type natriuretic peptides, and enhancing diuresis and natriuresis.

Sacubitril/valsartan showed an overwhelming superiority to enalapril in patients with HFrEF in the landmark PARADIGM-HF trial in 2014[6]. In the following years, a plethora of data has shown the beneficial effects of ARNIs on remodeling, arrhythmias, functional mitral regurgitation, rehospitalization, and mortality, both in the ambulatory and acute settings.

PARADIGM-HF trial[6]

The PARADIGM-HF trial was a large (N = 8,442), multicenter, prospective, RCT of sacubitril/valsartan (S/V, target dose 97/103 mg twice daily) compared with enalapril in patients with New York Heart Association (NYHA) class II–IV HF and a left ventricular ejection fraction (LVEF) of ≤40%[5]. ARNI treatment (S/V) was well-tolerated and was associated with 20% reduction in the composite endpoint of death from CV causes, or hospitalization for HF. In fact, the ARNI group has less prevalence of hyperkalemia and acute kidney injury (AKI), despite experiencing more frequent symptomatic hypotension.

Several post-hoc analyses of the PARADIGM-HF trial have established the greater efficacy of S/V, compared with ACEi/ARB, in terms of rates of CV death, HF hospitalization, all-cause mortality, worsening HF, and sudden cardiac death[7]. Additionally, S/V superiority over enalapril was maintained across different geographic regions[8], age groups[9], and regardless of LVEF[10]. Patients with milder HF and more severe HF had comparable relative benefit from ARNI therapy[11]. Moreover, patients with a recent HF hospitalization were as likely to benefit from ARNI therapy as clinically stable patients without prior HF hospitalization[12]. S/V reduced all-cause and HF readmissions at 30 and 60 days, and worsening HF compared with enalapril[13,14]. Even a dose lower than the target dose of an ARNI maintained efficiency superior to that of enalapril. Furthermore, the benefit of S/V over enalapril was consistent regardless of background therapy or previous coronary revascularization[15]. Long-term renal function seemed protected to a larger extent by S/V compared with ACEi, and, importantly, these data were consistent across the spectrum of LVEF[16–18]. Of note, S/V partially mitigates the risk of hyperkalemia when associated with MRAs[19]. ARNI therapy also improved quality of life and physical and social activities compared with enalapril[20,21]. S/V improved glycemic control in patients with diabetes and delayed the onset of insulin initiation[22].

Short comment

Based on the PARADIGM-HF trial results, S/V was approved for use for patients with HFrEF, but many groups were not represented in the study population, such as those with new-onset HF, those naïve to RAAS inhibition, or those in whom initial titration to the target dose was not successful. Further studies addressed those groups specifically to help implement ARNI in clinical practice.


PROVE-HF was an open-label study involving 794 patients with chronic NYHA II–IV HFrEF who were assigned to S/V, and evaluated by echocardiography and NT-pro-brain natriuretic peptide (NT-pro-BNP) levels at 0, 6, and 12 months[23]. The study demonstrated significant 37% reduction in NT-proBNP level after initiation of ARNI therapy, an average LVEF increase of 9.4% with decreased left ventricular (LV) and left atrial volumes, and improvement in diastolic function measured by the E/e’ ratio. Results were consistent among different patient groups (new-onset HF, ACEi-naïve patients, or those not achieving the target S/V dose).

Short comment

The PROVE-HF study demonstrated the benefit of ARNI on structural reverse remodeling and enhancement of systolic and diastolic function.


This double-blinded RCT enrolled 498 NYHA II–IV patients including ACEi-naïve subjects, randomized to a “condensed” up-titration group (titration in 3 weeks) or “conservative” up-titration group (titration in 6 weeks)[24]. Treatment success, defined as tolerability of the drug, was achieved by 77.8% of the patients in the “condensed” arm and in 84.3% of patients in the “conservative” arm (P = 0.078). The results of TITRATION showed that patients not on ACEi/ARBs or those on low doses of either may reach and maintain target doses of S/V when the titration is more gradual.

Short comment

The TITRATION study demonstrated that S/V may be titrated in 3 weeks in the majority of patients, except in ACEi/ARB-naïve patients or those on a low background dose of ACEi/ARBs, wherein the titration should be more gradual. Moreover, a single episode of drug intolerance does not necessarily mean that the target dose cannot be reached more gradually in the future.


PIONEER included 881 patients hospitalized with decompensated HFrEF, a third of whom had de novo HF, and 52% not taking an ACEi/ARB during an acute HF hospitalization[25]. Randomization was performed after the patients were hemodynamically stabilized (systolic blood pressure > 100 mm Hg with no need for escalation of diuretics or recent use of intravenous (IV) vasodilators or inotropes) into an ARNI therapy group and enalapril treatment group. ARNI therapy showed significant NT-proBNP level reduction compared with enalapril therapy (47% vs. 25%), with no significant differences in symptomatic hypotension, worsening renal function, angioedema, and hyperkalemia. The ARNI group showed 44% reduction in repeated HF hospitalizations.

Short comment

The PIONEER study showed that it was safe and effective to initiate ARNI therapy in acute HF, de novo HF, and in ACEi-naive patients. These game-changing data suggest that it is reasonable to start S/V immediately after hemodynamic stabilization even in a patient with first-diagnosed HF, without the necessity to undergo ACEi/ARB therapy or wait for ambulation[26].


The TRANSITION study (n = 1,002) was an open-label study comparing two treatment initiation modalities of S/V: pre-discharge or in the first 14 days post-discharge[27]. Comparable proportions of patients met the primary endpoint of tolerability of the drug (45.4% vs. 50.7%; risk ratio 0.90). Discontinuation due to adverse events occurred in 7.3% vs. 4.9% of patients (RR 1.49; 95% CI 0.90–2.46). Twenty-four percent of the patients were ACEi/ARB naïve and 29% had de novo HF.

Short comment

The TRANSITION study confirmed the results of PIONEER, showing feasibility and safety of early S/V initiation, even in de novo HF and RAAS inhibitor-naïve patients.


MRAs (spironolactone and eplerenone) block aldosterone receptors and, with different degrees of affinity, block corticosteroids, androgens, and progesterone receptors. MRAs are recommended in symptomatic patients with HFrEF and an LVEF of ≤35% to reduce mortality and HF hospitalization[27].


This trial randomized 1,663 NYHA III-IV patients with an LVEF of <35% to spironolactone or placebo, showing 30% reduction in death rate related to worsening HF and arrhythmic ventricular events. Moreover, the rate of hospitalization for worsening HF was 35% lower in the spironolactone group (P < 0.001).[28,29]

Short comment

Spironolactone significantly reduced both composite and two-individual endpoints of death and hospitalization. However, in this dated trial, few patients were on ACEis, hampering the generalization process to the contemporary HFrEF population.


EPHESUS was a double-blind, placebo-controlled RCT of 6,632 patients comparing eplerenone and placebo in post-acute myocardial infarction (MI) HFrEF, which confirmed the efficacy of aldosterone blockade on reduction of mortality from all causes (P = 0.008) and CV causes (P = 0.005)[30]. Aldosterone blockade also reduced the rate of sudden cardiac death (P = 0.03).

Short comment

The efficacy of spironolactone is reproduced with a newer drug with much fewer endocrine side effects. Initiating MRA in the acute phase for post-MI patients is safe and well-tolerated[31].


This trial randomized 2,737 NYHA II–IV patients with an LVEF of <35% to eplerenone or placebo group. Results showed 37% reduction in the composite endpoint of CV death or HF hospitalization. These results are still significant in each endpoint individually[32].

Short comment

Compared with older trials, these patients were already on beta-blockers and ACEi/ARBs at the maximally tolerated dose, highlighting the mortality benefit of MRAs even in mildly symptomatic patients already on “well-titrated” baseline therapy.


Beta-blockers are competitive antagonists for endogenous catecholamines at adrenergic beta receptors, with negative chronotropic and inotropic responses. The drugs approved for HFrEF treatment (bisoprolol, carvedilol, nebivolol, and metoprolol succinate extended-release drug) reduce morbidity and mortality in symptomatic patients with HFrEF.

A meta-analysis of the major beta-blocker trials in HFrEF neither showed benefits nor increased risks on hospital admissions and mortality in the subgroup of patients with atrial fibrillation[33].

Beta-blockers reduce mortality in patients with a history of MI and LV systolic dysfunction, even if they are asymptomatic.

The four pivotal beta-blocker placebo-controlled randomized trials in HF are COPERNICUS (carvedilol)[34], CIBIS-II (bisoprolol)[35], MERIT-HF (metoprolol succinate)[36], and SENIORS (nebivolol)[37].


This RCT compared carvedilol and placebo in 2,289 patients with NYHA III-IV HFrEF, showing reduction in all-cause mortality and the all-cause hospitalization rate by 24% (P < 0.001). These patients spent 40% fewer days in the hospital for HF (P < 0.0001) and reported better quality of life. The beneficial effects of carvedilol were maintained in patients with severely impaired LVEF (<25%)[35].

Short comment

Patients in COPERNICUS were sick with severely reduced LVEF (<25%) and significant comorbidity, but they showed no hemodynamic deterioration after beta-blocker therapy. Furthermore, the efficacy was significantly greater than that of placebo, leading to the trial being completed early after 10.4 months. However, since Intensive Care Unit patients and those receiving IV vasodilators were excluded, we should wait for stabilization and follow a gradual approach in this population.


This RCT showed 24% mortality reduction with bisoprolol (n = 1,327) versus placebo (n = 1,320) in NYHA III-IV patients with an LVEF of <35% (P < 0.001). The drug showed a marked anti-arrhythmic effect compared with placebo, similar to other beta-blockers.[36]

Short comment

In this population, the greatest benefit was appreciated in ischemic cardiomyopathy and NYHA functional class III.


MERIT-HF enrolled 3,991 NYHA ≥II HFrEF patients with an LVEF of <40%, and randomized them to metoprolol succinate (extended-release) once daily or placebo. The investigational drug reduced all-cause mortality by 34% (P < 0.001), risk of CV death by 38% (P < 0.001), risk of sudden death by 41% (P < 0.001), and risk of death from aggravated HF by 49% (P = 0.002)[36].

Short comment

This trial closely reproduced the beneficial effects of beta-blockade found in both COPERNICUS and CIBIS-II. Once daily extended-release metoprolol succinate guarantees even and prolonged beta-blockade over 24 h, compared with metoprolol tartrate. The latter molecule showed increased mortality compared with carvedilol and is not recommended in HFrEF.


SENIORS enrolled elderly patients (>70 years of age) with a wide range of NYHA class (I–IV) and LVEF; the mean LVEF was 36%, but 35% of patients had an LVEF of >35%. Patients were randomized to nebivolol (n = 1,067) or placebo (n = 1,061).

Combined all-cause mortality and the CV hospitalization rate were reduced by 14% (P = 0.04)[37].

Short comment

Apparently, nebivolol showed inferior relative risk reduction in all-cause mortality and CV hospitalization compared with the other three beta-blockers. Possible explanations for the different results are as follows: treatment with a different beta-blocker, inclusion of patients with a different type of HF (both reduced and preserved LVEF), use of a different primary endpoint, and longer duration of follow-up (all three previous trials were stopped early).


SGLT2 proteins are expressed in the proximal convoluted tubules of the kidneys and are responsible for reabsorption of approximately 90% of filtered glucose, together with sodium, making them the ideal target for blood glucose reduction by glycosuria in diabetes.

A new drug class of four molecules was developed to inhibit SGLT2: dapagliflozin, empagliflozin, canagliflozin, and sotagliflozin.

Inhibiting SGLT2 can lower the threshold for glycosuria from the usual threshold (blood glucose 180 mg/dL) to as low as 40 mg/dL. People with genetically non-functional SGLT2 and severe glycosuria are usually healthy, with a low risk of hypotension and hypoglycemia, suggesting the safety of SGLT2 inhibition even in patients without non-diabetes.

The reduced incidence of HF and cardiac events and the preservation of renal function with SGLT2i in primary prevention diabetes trials was shown by a meta-analysis of EMPA-REG OUTCOME, CANVAS, CREDENCE, and DECLARE-TIMI 58[38,39]. It hypothesized the beneficial effect of these drugs in HF, independently from diabetes mellitus. Two major trials were conducted to explore this effect: DAPA-HF[40] and EMPEROR-Reduced[41]. These trials showed a similar beneficial effect both in diabetic and non-diabetic HF patients, suggesting that a different mechanism of action of SGLT2i, apart from glycosuria, may play a beneficial role in HF. Both DAPA-HF and EMPEROR-Reduced trials are reassuring about the safety of combining an ARNI and SGLT2i. In fact, a recent sub-analysis of EMPEROR-Reduced[41] showed an increased beneficial effect of empagliflozin when used with an ARNI, instead of an ACEi/ARB. Empagliflozin reduced the combined endpoint of CV death or hospitalization by 36% with ARNI versus 23% with ACEi (P = 0.0008). Moreover, empagliflozin slowed the estimated glomerular filtration rate (eGFR) deterioration by 1.92 mL/min/m2 per year when combined with an ARNI, compared with 1.72 mL/min/m2 per year when combined with an ACEi/ARB (P < 0.0001). In the placebo group, these differences were not evident in the ARNI versus non-ARNI groups, suggesting a causal role of empagliflozin, and not a baseline difference in the study groups.


This landmark phase III, placebo-controlled RCT enrolled 4,744 patients with NYHA II–IV HF, elevated NT-pro-BNP levels, and an LVEF of <40%. Patients were randomized to receive either dapagliflozin 10 mg or placebo, in addition to an ACEi/ARB or ARNI, a beta-blocker, an MRA, and cardiac resynchronization therapy (CRT). The primary outcome was a composite of CV death and worsening HF, requiring hospitalization, or an unplanned outpatient visit. Dapagliflozin was associated with 26% reduction in the primary endpoint (16% vs. 21.2%, P < 0.001), 18% reduction in CV mortality, and 30% reduction in worsening HF. The effect started as early as 6 months after randomization. Dapagliflozin was equally effective in patients with type 2 diabetes or in patients without diabetes (55% of patients). Moreover, volume depletion, renal dysfunction, and hypoglycemia did not differ between the groups. Interestingly, significant hypoglycemia events were rare and occurred in patients with diabetes only, were mostly treated with other medications, including insulin.

Finally, the use of dapagliflozin also resulted in fewer symptoms of HF, as measured by the Kansas City Cardiomyopathy Questionnaire.

Short comment

DAPA-HF introduces a new class of safe and effective drugs in HFrEF, with similar effects in patients with and without diabetes. This new class of drugs has been effective in changing mortality, reducing hospitalizations, and improving quality of life in patients on full poly-pharmacological and device treatment, with effects already evident after 6 months.


This trial randomized 3,730 patients with NYHA II–IV HF, LVEF of ≤40%, and elevated NT-pro-BNP levels to receive empagliflozin 10 mg or placebo. All patients were on optimal medical therapy, including beta-blockers, ARNIs or ACEi/ARBs, MRAs, and a CRT if indicated. The combined endpoint of CV death or hospitalization for HF reduced by 25% (P < 0.001); the rate of hospitalization alone was reduced by 30%, and CV mortality alone was reduced by 8%.

Half the patients had a history of diabetes, with no difference in the magnitude of the protective effect of empagliflozin on CV outcomes in patients with and without diabetes (HR 0.72 vs. 0.78, P = NS), both statistically significant compared with placebo.

The annual rate of decline in eGFR was slower in the empagliflozin group than in the placebo group (–0.55 vs. –2.28 mL/min/1.73 m2 per year, P < 0.001), with lower incidence of mayor renal adverse events (chronic dialysis, renal transplantation, or profound and sustained decline in eGFR), that occurred in 1.6% of patients in the empagliflozin arm and 3.1% of patients in the placebo arm.

Uncomplicated genital tract infection was reported more frequently in the empagliflozin group[41].

Short comment

This trial closely reproduced the results of DAPA-HF, showing a probable class effect of SGLT2 inhibition, and confirming the data on the efficacy and excellent safety of SGLT2 inhibitors. The 50% reduction in renal events highlighted in the EMPEROR-Reduced trial is consistent, both in effect and size, with what was observed in large trials in chronic kidney disease[38].


The SOLOIST-WHF trial randomized 1,222 patients, recently hospitalized for worsening HF, to sotagliflozin or placebo. The study drug was initiated before or soon after discharge.

The primary composite endpoint was the total number of deaths from CV causes, and hospitalizations and urgent visits for HF. Sotagliflozin caused 33% reduction in this endpoint, with no difference in AKI between the study groups[42].

Short comment

The results of the SOLOIST-WHF trial confirm the class effect of SGLT2i when started in the acute setting of recently decompensated HF. Importantly, a pre-specified analysis of patients with an LVEF of >50% showed consistent benefit in these patients compared with patients with an LVEF of <50%.


EMPULSE is a double bind trial in which 530 patients with a primary diagnosis of acute de novo or decompensated chronic HF regardless of LVEF were randomly assigned to receive 10 mg empagliflozin once daily or placebo. Patients were randomized in-hospital when clinically stable and were treated for up to 90 days. The primary outcome was a clinical benefit defined as a hierarchical composite of death from any cause, number of HF events, and time to first HF event.

Empagliflozin showed a net clinical benefit compared with placebo (P = 0.0054), meeting the primary endpoint for both acute de novo and decompensated chronic HF, and was observed regardless of LVEF or the presence of diabetes.

Short comment

The results of the EMPULSE trial confirm that the initiation of SGLT2i in patients hospitalized for acute HF is well-tolerated and leads to a significant clinical benefit in the 90 days after treatment initiation.

Insights on the novel 4 aces approach and unsettled issues

The 4 aces approach has established a new paradigm for the treatment of HFrEF. As outlined in the current guidelines, HFrEF therapy should include a prompt inclusion of all four classes of life saving drugs, namely, RASI/ARNIs, beta-blockers, MRAs, and SGLT2is. However, there are some unsettled issues that need to be taken into consideration.

The crucial issue is the applicability of this new approach in the acute setting because there are limited data regarding the implementation of ARNIs, especially SGLT2is, during an acute decompensation event. Generally, the initiation of these novel compounds is suggested after clinical stabilization. Moreover, unresolved issues include the following: whether SGLT2is can be administered upfront, from the first day of HF admission, how this approach might impact kidney function, and whether this strategy might be performed by adding an SGLT2i on top of other diuretics or as a partial substitution of other diuretics.

In addition, SGTL2is are usually the last pillar added to the therapeutic armamentarium for patients with HFrEF. However, adding SGLT2is before ARNI/RASI, as suggested by a recently published perspective article, is worth consideration[44], and we formally support this approach due to the simplicity of clinical uptake of SGLT2i compounds (once a day) and the good safety outcomes (Figure 3). Nonetheless, we eagerly await prospective data on this point.

Figure 3:
Algorithm proposed by McMurray and Packer[43] for the implementation of foundational treatments for ambulatory patients with heart failure and a reduced ejection fraction.ARNI: angiotensin receptor neprilysin inhibitor; BP: blood pressure; MRA: mineralocorticoid receptor antagonist; SGLT2i: sodium-glucose cotransporter 2.

Other issues include findings from a post-hoc analysis of the DAPA-HF trial regarding the effect of dapagliflozin on reducing the risk of any serious ventricular arrhythmia, cardiac arrest, or sudden death when added to conventional therapy in patients with HFrEF[45]. These data need further confirmation and clarification of the possible mechanisms responsible for these effects. Furthermore, the PARADISE-MI study, an important trial in the setting of acute HF induced by MI, did not show a significant benefit of ARNI compared with ramipril in this peculiar population[46]. However, subgroup analyses and hypothesis generation in case of a neutral trial may help us better clarify the reasons for these unexpected findings. For example, the study of the possible benefit of ARNI in patients with a large anterior acute MI, or in those with different blood pressure thresholds, or with higher levels of BNP or troponin at baseline might be informative. Finally, the results of a post-hoc analysis of the FIGARO-DKD study demonstrate that finerenone reduces new-onset HF and improves other HF outcomes in patients with chronic kidney disease and type 2 diabetes, irrespective of a history of HF[47]. Thus, a novel compound among the MRA category might prove to be the MRA of choice in the 4 aces approach of HFrEF treatment, as suggested by the ARTS-HF trial[48].


The current paradigm of HFrEF multi-drug therapy is changing from a slow and stepwise approach, starting with 2 “aces” (beta-blocker and ACEi/ARB) and adding new classes only if the patient remains symptomatic with a low LVEF to a combination approach, with all four drug classes administered upfront. The new approach suggests starting immediately with a beta-blocker plus SGLT2i and rapidly in a few days to weeks, adding an ARNI, without the need to undergo ARB/ACEi and MRA therapy.

First, this approach is safe, and maybe safer than the standard approach; SGLT2is are nephroprotective and the combination of MRAs and ARNIs leads to low prevalence of hyperkalemia than MRAs plus ACEi/ARBs.

Second, this approach is backed by robust and rigorous meta-analyses and putative placebo analyses, showing improved survival and reduced hospitalization, assuring more disease-free life years the sooner the “4 aces” are started.

Third, this approach is intuitive and promising, especially in a young patient presenting with de novo HFrEF, where it seems reasonable to offer all the best therapy available upfront (if there is not a very good reason to wait) to boost remodeling, reduce myocardial fibrosis, improve diastolic function and functional mitral regurgitation, reduce left atrial size and atrial fibrillation risk, improve renal protection, avoid early rehospitalization, and reduce the risk of sudden death. It would probably offer maximal life expectancy gain, cut the costs, and could mean avoidance of internal cardioverter defibrillator implantation for primary prevention after 3 months.

Author contributions

ER, MG, ED, ES wrote original draft preparation, reviewed and edited the revised manuscript; VS and MS supervised and administrated the project. All authors reviewed and approved the manuscript..

Conflict of interest statement

ER, MG, ED, ES: None; VS is an employee of Novartis; MS reported personal fees from Novartis Pharmaceuticals, Astra Zeneca, Boehringer Ingelheim, Servier, Bayer.


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Angiotensin receptor neprilysin inhibitors; Heart failure with reduced ejection fraction; Optimal medical therapy; Sodium-glucose-cotransporter 2 inhibitors

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